OncoOne Research & Development GmbH, Vienna, Austria.
University of Catania, Department of Biomedical and Biotechnological Sciences, Catania, Italy.
Eur J Pharmacol. 2023 Oct 5;956:175997. doi: 10.1016/j.ejphar.2023.175997. Epub 2023 Aug 12.
Macrophage Migration Inhibitory Factor (MIF) is a pleiotropic inflammatory cytokine that emerged as a pivotal regulator in the pathogenesis of several autoimmune diseases including rheumatoid arthritis (RA). MIF occurs in two immunologically distinct conformational isoforms, indicated as reduced (redMIF) and oxidized MIF (oxMIF) where the latter exerts disease-related activities. In this study we demonstrate the presence of circulating oxMIF in RA patients and investigate the in vivo effects of an oxMIF-neutralizing antibody in a murine model of RA. By advanced antibody engineering we generated the fully human anti-oxMIF antibody ON104 with abolished effector functions. The therapeutic potential of ON104 was tested in a model of Collagen-Induced Arthritis (CIA) in DBA/1j mice. At disease onset, the mice received ON104 twice a week for three weeks. Clinical symptoms were assessed daily, and histological examinations of the joints were performed at the end of the study. Antibody ON104, specifically targeting human and murine oxMIF, is highly affine and does not elicit effector functions in vitro. The treatment of CIA mice with ON104 profoundly modulated disease progression with marked amelioration of clinical signs of arthritis that was associated with reduced synovial and cartilage damage and reduced F4/80-positive macrophages in the joints. These data prove that oxMIF is a relevant target in a well-known model of human RA and its specific neutralization by the antibody ON104 ameliorates clinical and histological signs of the disease in the so-treated mice. Thus, ON104 represents a new and promising treatment option for RA and possibly other autoimmune diseases.
巨噬细胞移动抑制因子（MIF）是一种多功能炎症细胞因子，作为几种自身免疫性疾病（包括类风湿关节炎（RA））发病机制中的关键调节剂而出现。MIF 存在两种免疫上不同的构象异构体，分别表示为还原型（redMIF）和氧化型 MIF（oxMIF），后者发挥与疾病相关的活性。在这项研究中，我们在 RA 患者中证明了循环 oxMIF 的存在，并研究了 oxMIF 中和抗体在 RA 小鼠模型中的体内效应。通过先进的抗体工程，我们生成了完全人源抗 oxMIF 抗体 ON104，其丧失了效应功能。ON104 的治疗潜力在 DBA/1j 小鼠的胶原诱导关节炎（CIA）模型中进行了测试。在疾病发作时，每周两次给小鼠注射 ON104，持续 3 周。每天评估临床症状，并在研究结束时对关节进行组织学检查。ON104 特异性针对人源和鼠源 oxMIF，亲和力高，在体外不引发效应功能。用 ON104 治疗 CIA 小鼠可显著调节疾病进展，关节炎的临床症状明显改善，同时伴有滑膜和软骨损伤减少，以及关节中 F4/80 阳性巨噬细胞减少。这些数据证明 oxMIF 是一种相关靶点，在著名的人类 RA 模型中，其特异性中和抗体 ON104 可改善治疗小鼠的临床和组织学疾病迹象。因此，ON104 代表了一种新的、有前途的 RA 治疗选择，并且可能对其他自身免疫性疾病也有治疗作用。
